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Background Aims: The prevalence of chronic wounds continues to be a burden in human medicine. Methicillin-resistant Staphylococcus aureus (MRSA) is commonly isolated from infected wounds. MRSA infections primarily delay healing by impairing local immune cell functions. This study aimed to investigate the potential of mesenchymal stromal cell (MSC)-secreted bioactive factors, defined as the secretome, to improve innate immune responses in vivo. MSCs were isolated from the bone marrow of horses, which serve as valuable translational models for wound healing. The MSC secretome, collected as conditioned medium (CM), was evaluated in vivo using mouse models of acute and MRSA-infected skin wounds., Methods: Punch biopsies were used to create two full-thickness skin wounds on the back of each mouse. Acute wounds were treated daily with control medium or bone marrow-derived MSC (BM-MSC) CM. The antibiotic mupirocin was administered as a positive control for the MRSA-infected wound experiments. Wounds were photographed daily, and wound images were measured to determine the rate of closure. Trichrome staining was carried out to examine wound tissue histologically, and immunofluorescence antibody binding was used to assess immune cell infiltration. Wounds in the MRSA-infected model were swabbed for quantification of bacterial load., Results: Acute wounds treated with BM-MSC CM showed accelerated wound closure compared with controls, as illustrated by enhanced granulation tissue formation and resolution, increased vasculature and regeneration of hair follicles. This treatment also led to increased neutrophil and macrophage infiltration. Chronic MRSA-infected wounds treated with BM-MSC CM showed reduced bacterial load accompanied by better resolution of granulation tissue formation and increased infiltration of pro-healing M2 macrophages compared with control-treated infected wounds., Conclusions: Collectively, our findings indicate that BM-MSC CM exerts pro-healing, immunomodulatory and anti-bacterial effects on wound healing in vivo, validating further exploration of the MSC secretome as a novel treatment option to improve healing of both acute and chronic wounds, especially those infected with antibiotic-resistant bacteria., Competing Interests: Declaration of competing interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Phage therapy appears to be a promising approach to tackle multidrug-resistant bacteria, including staphylococci. However, most anti-staphylococcal phages have been characterized in Staphylococcus aureus , while a limited number of studies investigated phage activity against S. epidermidis . We studied the potential of phage training to extend the host range of two types of anti- S . aureus phages against S. epidermidis isolates. The Appelmans protocol was applied to a mixture of Kayvirus and a mixture of Silviavirus phages repeatedly exposed to seven S . epidermidis strains representative of nosocomial-associated sequence types (ST), including the world-wide disseminated ST2. We observed increased activity only for the Kayvirus mixture against two of these strains (ST2 or ST35). Phage subpopulations isolated from the training mixture using these two strains (five/strain) exhibited different evolved phenotypes, active only against their isolation strain or strains of the same ST. Of note, 16/47 ST2 strains were susceptible to one of the groups of trained phages. A comparative genomic analysis of ancestral and trained phage genomes, conducted to identify potential bacterial determinants of such specific activity, found numerous recombination events between two of the three ancestors. However, a small number of trained phage genes had nucleotide sequence modifications impacting the corresponding protein compared to ancestral phages, two to four of them per phage genome being specific of each group of phage subpopulations exhibiting different host range. The results suggest that anti- S . aureus phages can be adapted to S. epidermidis isolates but with inter- and intra-ST specificity.Importance S. epidermidis is increasingly recognized as a threat for public health. Its clinical importance is notably related to multidrug resistance. Phage therapy is one of the most promising alternative therapeutic strategies to antibiotics. Nonetheless, only very few phages active against this bacterial species have been described. In the present study, we showed that phage training can be used to extend the host range of polyvalent Kayvirus phages within the Staphylococcus genera to include S. epidermidis species. In the context of rapid development of phage therapy, in vitro forced adaptation of previously characterized phages could be an appealing alternative to fastidious repeated isolation of new phages to improve the therapeutic potential of a phage collection., Competing Interests: The authors declare no conflict of interest.

Biofilm infection and impaired healing of chronic wounds are posing tremendous challenges in clinical practice. In this study, we presented a versatile antimicrobial hydrogel capable of delivering nitric oxide (NO) in a controllable manner to dissipate biofilms, eliminate microorganisms, and promote the healing of chronic wounds. This hydrogel was constructed by Schiff-base crosslinking of oxidized dextran and antimicrobial peptide ε-poly-lysine, further encapsulating photothermal nanoparticles bearing NO donor. This hydrogel could continuously and slowly release NO, effectively dissipating biofilms, and promoting the proliferation of mouse fibroblasts and the migration of endothelial cells. Upon exposure to NIR laser irradiation, the hydrogel generated hyperthermia and rapidly released NO, resulting in the efficient elimination of a broad spectrum of drug-resistant Gram-positive/negative bacterial and fungal biofilms through the synergistic effects of NO, photothermal therapy, and the antibacterial peptide. Notably, the hydrogel demonstrated exceptional in vivo therapeutic outcomes in accelerating the healing process of mice diabetic wounds infected with methicillin-resistant Staphylococcus aureus by successfully eliminating biofilm infection, regulating inflammation, and facilitating angiogenesis and collagen deposition. Overall, this proposed hydrogel shows great promise in accommodating the various demands of the complex repair process of chronic wounds infected with biofilms. STATEMENT OF SIGNIFICANCE: The presence of biofilm infections and underlying dysfunctions in the healing process made chronic wound become stuck in the inflammation stage and difficult to heal. This work developed a NIR laser-modulated three-stage NO-releasing versatile antimicrobial hydrogel (DEPN) exhibiting good therapeutic efficacy for chronic wound. This DEPN hydrogel could inherently and slowly released NO to disperse biofilm. Upon NIR laser irradiation, the DEPN hydrogel generated hyperthermia and induced a rapid burst release of NO effectively eliminating a broad spectrum of drug-resistant bacterial and fungal biofilms. Subsequently, the DEPN hydrogel continually release NO slowly to promote the tissue remolding. This DEPN hydrogel displays great potential in treatment of chronic wounds infected with biofilm., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Photothermal therapy (PTT) encounters challenges of rapid thermal loss and potential tissue damage. In response, we propose a Heat-Boost and Lock implant coating strategy inspired by the thermal adaptation of biological membranes, enabling precise local photothermal utilization. This coating incorporates a poly(tannic acid) (pTA) bridging layer on implants, facilitating stable layer-by-layer integration of a black phosphorus (BP) photothermal layer and a top cell membrane Heat-Boost and Lock layer. The cell membrane layer significantly curtails photothermal loss (extending the heat retention by 17.62%) and stores energy within its phospholipid bilayer, boosting photothermal effects near implants (achieving a temperature increasement of 275%). Theoretical analysis indicates that these local heat preservation properties of the cell membrane arise from its low thermal conductivity and phase-change properties. In a Staphylococcus aureus -infected bone implant model, our coating demonstrates precise antibacterial action around implants (reach an antibacterial ratio of 99.52%). The synergetic locking function of cell membrane and pTA delays BP biodegradation, ensuring favorable photothermal stability and long-term osteo-inductive performance (increasing the bone volume fraction by 53.45%). Beyond providing an endogenic biointerface, this strategy extends the application of cell membrane in local thermal management, offering possibilities for effective and safe PTT modalities.

Wound infections, exacerbated by the prevalence of antibiotic-resistant bacterial pathogens, necessitate innovative antimicrobial approaches. Polymicrobial infections, often involving Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), present challenges due to biofilm formation and antibiotic resistance. Hypochlorous acid (HOCl), a potent antimicrobial agent, holds promise as an alternative therapy. An electrochemical bandage (e-bandage) that generates HOCl in situ via precise polarization controlled by a miniaturized potentiostat was evaluated for the treatment of murine wound biofilm infections containing both P. aeruginosa with "difficult-to-treat" resistance and MRSA. Previously, HOCl-producing e-bandage was shown to reduce murine wound biofilms containing P. aeruginosa alone. Here, in 5-mm excisional skin wounds containing 48-h biofilms comprising MRSA and P. aeruginosa combined, polarized e-bandage treatment reduced MRSA by 1.1 log 10 CFU/g ( P = 0.026) vs non-polarized e-bandage treatment (no HOCl production), and 1.4 log 10 CFU/g (0.0015) vs Tegaderm only controls; P. aeruginosa was similarly reduced by 1.6 log 10 CFU/g ( P = 0.0032) and 1.6 log 10 CFU/g ( P = 0.0015), respectively. For wounds infected with MRSA alone, polarized e-bandage treatment reduced bacterial load by 1.1 log 10 CFU/g ( P = 0.0048) and 1.3 log 10 CFU/g ( P = 0.0048) compared with non-polarized e-bandage and Tegaderm only, respectively. The e-bandage treatment did not negatively impact wound healing or cause tissue toxicity. The addition of systemic antibiotics did not enhance the antimicrobial efficacy of e-bandages. This study provides additional evidence for the HOCl-producing e-bandage as a novel antimicrobial strategy for managing wound infections, including in the context of antibiotic resistance and polymicrobial infections., Importance: New approaches are needed to combat the rise of antimicrobial-resistant infections. The HOCl-producing electrochemical bandage (e-bandage) leverages in situ generation of HOCl, a natural biocide, for broad-spectrum killing of wound pathogens. Unlike traditional therapies that may exhibit limited activity against biofilms and antimicrobial-resistant organisms, the e-bandage offers a potent, standalone solution that does not contribute to further resistance or require adjunctive antibiotic therapy. Here, we show the ability of the e-bandage to address polymicrobial infection by antimicrobial resistant clinical isolates of Staphylococcus aureus and Pseudomonas aeruginosa , two commonly isolated, co-infecting wound pathogens. Effectiveness of the HOCl-producing e-bandage in reducing pathogen load while minimizing tissue toxicity and avoiding the need for systemic antibiotics underscores its potential as a tool in managing complex wound infections., Competing Interests: R.P. reports grants from MicuRx Pharmaceuticals and BIOFIRE. R.P. is a consultant to PhAST, Day Zero Diagnostics, Abbott Laboratories, Sysmex, DEEPULL DIAGNOSTICS, S.L., Netflix, HealthTrackRx, and CARB-X. In addition, R.P. has a patent for Bordetella pertussis/parapertussis PCR issued, a patent for a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued. R.P. receives honoraria from Up-to-Date and the Infectious Diseases Board Review Course. H.B. holds a patent, "Electrochemical reduction or prevention of infections" (US20180207301A1), which refers to the electrochemical scaffold upon which the current design of e-bandage is based.

The antibacterial efficacy and specificity of lytic bacteriophages (phages) make them promising therapeutics for treatment of multidrug-resistant bacterial infections. Restricted penetration of phages through the protective matrix of biofilms, however, may limit their efficacy against biofilm infections. Here, engineered polymers were used to generate noncovalent phage-polymer nanoassemblies (PPNs) that penetrate bacterial biofilms and kill resident bacteria. Phage K, active against multiple strains of Staphylococcus aureus , including methicillin-resistant S. aureus (MRSA), was assembled with cationic poly(oxanorbornene) polymers into PPNs. The PPNs retained phage infectivity, while demonstrating enhanced biofilm penetration and killing relative to free phages. PPNs achieved 3-log 10 bacterial reduction (∼99.9%) against MRSA biofilms in vitro. PPNs were then incorporated into Poloxamer 407 (P407) hydrogels and applied onto in vivo wound biofilms, demonstrating controlled and sustained release. Hydrogel-incorporated PPNs were effective in a murine MRSA wound biofilm model, showing a 1.5-log 10 reduction in bacterial load compared to a 0.5 log reduction with phage K in P407 hydrogel. Overall, this work showcases the therapeutic potential of phage K engineered with cationic polymers for treating wound biofilm infections.

The limited and unstable absorption of excess exudate is a major challenge during the healing of infected wounds. In this study, a highly stable, multifunctional Janus dressing with unidirectional exudate transfer capacity is fabricated based on a single poly(lactide caprolactone) (PLCL). The success of this method relies on an acid hydrolysis reaction that transforms PLCL fibers from hydrophobic to hydrophilic in situ. The resulting interfacial affinity between the hydrophilic/phobic PLCL fibers endows the Janus structure with excellent unidirectional liquid transfer and high structural stability against repeated stretching, bending, and twisting. Various other functions, including wound status detection, antibacterial, antioxidant, and anti-inflammatory properties, are also integrated into the dressing by incorporating phenol red and epigallocatechin gallate. An in vivo methicillin-resistant Staphylococcus aureus-infected wound model confirms that the Janus dressing, with the capability to remove exudate from the infected site, not only facilitates epithelialization and collagen deposition, but also ensures low inflammation and high angiogenesis, thus reaching an ideal closure rate up to 98.4% on day 14. The simple structure, multiple functions, and easy fabrication of the dressing may offer a promising strategy for treating chronic wounds, rooted in the challenges of bacterial infection, excessive exudate, and persistent inflammation., (© 2024 Wiley‐VCH GmbH.)

Maximal standard-of-care (SOC) management could not stop the life-threatening progression of a necrotizing fasciitis induced by Panton-Valentine Leukocidin-producing Methicillin-Resistant Staphylococcus aureus (MRSA) in a 12-year-old boy. Multi-route phage therapy was initiated along with antibiotics against Staphylococcus aureus, Pseudomonas aeruginosa and Stenotrophomonas maltophilia , eventually leading to full recovery with no reported adverse events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Van Nieuwenhuyse, Balcaen, Chatzis, Haenecour, Derycke, Detaille, Clément de Cléty, Boulanger, Belkhir, Yombi, De Greef, Cornu, Docquier, Lentini, Menten, Rodriguez-Villalobos, Verroken, Djebara, Merabishvili, Griselain, Pirnay, Houtekie and Van der Linden.)

Background: Cystic fibrosis (CF) patients are prone to recurrent multi-drug-resistant (MDR) bacterial lung infections. Under this scenario, phage therapy has been proposed as a promising tool. However, the limited number of reported cases hampers the understanding of clinical outcomes. Anti-phage immune responses have often been overlooked and only described following invasive routes of administration., Methods: Three monophage treatments against Staphylococcus aureus and/or Pseudomonas aeruginosa lung infections were conducted in cystic fibrosis patients. In-house phage preparations were nebulized over 10 days with standard-of-care antibiotics. Clinical indicators, bacterial counts, phage and antibiotic susceptibility, phage detection, and immune responses were monitored., Findings: Bacterial load was reduced by 3-6 log in two of the treatments. No adverse events were described. Phages remained in sputum up to 33 days after completion of the treatment. In all cases, phage-neutralizing antibodies were detected in serum from 10 to 42 days post treatment, with this being the first report of anti-phage antibodies after nebulized therapy., Conclusions: Nebulized phage therapy reduced bacterial load, improving quality of life even without bacterial eradication. The emergence of antibodies emphasizes the importance of long-term monitoring to better understand clinical outcomes. These findings encourage the use of personalized monophage therapies in contrast to ready-to-use cocktails, which might induce undesirable antibody generation., Funding: This study was supported by the Spanish Ministry of Science, Innovation and Universities; Generalitat Valenciana; and a crowdfunding in collaboration with the Spanish Cystic Fibrosis Foundation., Competing Interests: Declaration of interests P.D.-C. is cofounder of Evolving Therapeutics SL and a member of its scientific advisory board, and P.E.T. is cofounder of Felix Biotechnology, Inc., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The rise of methicillin-resistant Staphylococcus aureus (MRSA) poses a significant challenge in clinical settings due to its ability to evade conventional antibiotic treatments. This overview explores the potential of immunomodulatory strategies as alternative therapeutic approaches to combat MRSA infections. Traditional antibiotics are becoming less effective, necessitating innovative solutions that harness the body's immune system to enhance pathogen clearance. Recent advancements in immunotherapy, including the use of antimicrobial peptides, phage therapy, and mechanisms of immune cells, demonstrate promise in enhancing the body's ability to clear MRSA infections. However, the exact interactions between these therapies and immunomodulation are not fully understood, underscoring the need for further research. Hence, this review aims to provide a broad overview of the current understanding of non-traditional therapeutics and their impact on immune responses, which could lead to more effective MRSA treatment strategies. Additionally, combining immunomodulatory agents with existing antibiotics may improve outcomes, particularly for immunocompromised patients or those with chronic infections. As the landscape of antibiotic resistance evolves, the development of effective immunotherapeutic strategies could play a vital role in managing MRSA infections and reducing reliance on traditional antibiotics. Future research must focus on optimizing these approaches and validating their efficacy in diverse clinical populations to address the urgent need for effective MRSA management strategies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Burn wounds are a major burden, with high mortality rates due to infections. Staphylococcus aureus is a major causative agent of burn wound infections, which can be difficult to treat because of antibiotic resistance and biofilm formation. An alternative to antibiotics is the use of bacteriophages, viruses that infect and kill bacteria. We investigated the efficacy of bacteriophage therapy for burn wound infections, in both a porcine and a newly developed human ex vivo skin model. In both models, the efficacy of a reference antibiotic treatment (fusidic acid) and bacteriophage treatment was determined for a single treatment, successive treatment, and prophylaxis. Both models showed a reduction in bacterial load after a single bacteriophage treatment. Increasing the frequency of bacteriophage treatments increased bacteriophage efficacy in the human ex vivo skin model, but not in the porcine model. In both models, prophylaxis with bacteriophages increased treatment efficacy. In all cases, bacteriophage treatment outperformed fusidic acid treatment. Both models allowed investigation of bacteriophage-bacteria dynamics in burn wounds. Overall, bacteriophage treatment outperformed antibiotic control underlining the potential of bacteriophage therapy for the treatment of burn wound infections, especially when used prophylactically., Competing Interests: The authors declare no conflict of interest.

Bacteria-infected wounds pose challenges to healing due to persistent infection and associated damage to nerves and vessels. Although sonodynamic therapy can help kill bacteria, it is limited by the residual oxidative stress, resulting in prolonged inflammation. To tackle these barriers, novel 4 octyl itaconate-coated Li-doped ZnO/PLLA piezoelectric composite microfibers are developed, offering a whole-course "targeted" treatment under ultrasound therapy. The inclusion of Li atoms causes the ZnO lattice distortion and increases the band gap, enhancing the piezoelectric and sonocatalytic properties of the composite microfibers, collaborated by an aligned PLLA conformation design. During the infection and inflammation stages, the piezoelectric microfibers exhibit spatiotemporal-dependent therapeutic effects, swiftly eliminating over 94.2 % of S. aureus within 15 min under sonodynamic therapy. Following this phase, the microfibers capture reactive oxygen species and aid macrophage reprogramming, restoring mitochondrial function, achieving homeostasis, and shortening inflammation cycles. As the wound progresses through the healing stages, bioactive Zn 2+ and Li  +  ions are continuously released, improving cell recruitment, and the piezoelectrical stimulation enhances wound recovery with neuro-vascularization. Compared to commercially available dressings, our microfibers accelerate the closure of rat wounds (Φ = 15 mm) without scarring in 12 days. Overall, this "one stone, four birds" wound management strategy presents a promising avenue for infected wound therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Fracture-related infections (FRIs), particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA), are challenging to treat. This study designed and evaluated a hydrogel loaded with a cocktail of bacteriophages and vancomycin (1.2 mg/mL). The co-delivery hydrogel showed 99.72% reduction in MRSA biofilm in vitro. The hydrogel released 54% of phages and 82% of vancomycin within 72 h and maintained activity for eight days, in vivo the co-delivery hydrogel with systemic antibiotic significantly reduced bacterial load by 0.99 log10 CFU compared to controls, with active phages detected in tissues at euthanasia (2 × 10 3 PFU/mL). No phage resistance was detected in the phage treatment groups, and serum neutralization resulted in only a 20% reduction in phage count. In this work, we show that a phage-antibiotic co-delivery system via CMC hydrogel is a promising adjunct to systemic antibiotic therapy for MRSA-induced FRI, highlighting its potential for localized, sustained delivery and improved treatment outcomes., (© 2024. The Author(s).)

Sonodynamic therapy (SDT) is a promising strategy to treat deep-seated bacterial infections with good tissue penetration and spatiotemporal controllability. However, the low ROS generation efficiency of current sonosensitizers limits the development of SDT. Herein, we report a porphyrin derivative, TAPyPP-2, the sonodynamic activity of which is enhanced with less oxygen dependence by tuning its molecular assembly behavior. TAPyPP-2 can spontaneously form an ultra-small nano-assembly with a diameter of 6 nm in water by conjugation with primary amine salt-decorated pyridinium via π-π staking. The ultra-small assembly behavior can lower the energy gap between singlet and triplet states to 0.01 eV and promote the separation of holes and electrons, which facilitates ROS generation under ultrasound irradiation, in particular type I ROS. The unique hydrophilic ratio and positive charges endow TAPyPP-2 with superior abilities to interact with Staphylococcus aureus , resulting in extremely high sonodynamic antibacterial activity. Therefore, TAPyPP-2 successfully kills Staphylococcus aureus bacteria in the enclosed cavity of synovial joint and achieves effective SDT of septic arthritis. This work is anticipated to motivate enormous interest in the development of efficient SDT.

Rationale: Iliopsoas abscess is a rare acute medical condition. It usually occurs because of the spread of infection from adjacent structures and hematogenous spread. Clinical features include fever, backache, radiating nerve root pain, and leg weakness. When sepsis occurs, prompt recognition is required to initiate appropriate antimicrobial therapy and surgical drainage., Patient Concerns: A 65-year-old male presented to the outpatient department with a 2-day history of lower back, hip, and leg pain, for which analgesics were administered. During hospitalization, he experienced deterioration, becoming febrile, hypoxic, hypotensive, tachycardiac, and delirious., Interventions: The patient was then intubated and ventilated. His family reported an additional history of acupuncture for back pain, which sustained an inflamed wound on his right forearm. Abdominal computed tomography was performed, which confirmed bilateral iliopsoas abscess without involvement of intra-abdominal organs. A preliminary report of blood culture revealed Gram-positive cocci. Echocardiography showed vegetation on the aortic valve, and moderate aortic regurgitation was sustained. He was started on vancomycin along with piperacillin-tazobactam. Ultrasound-guided percutaneous drainage was inserted into the bilateral abscess. Pus and blood yielded methicillin-sensitive Staphylococcus aureus. He remained septic. The repeat computed tomography showed the right abscess enlarged. A repeated echocardiogram showed that the vegetation increased. Further incision and surgical drainage were performed with continuous wash-out., Outcome: His condition improved after management and he was discharged to a regional hospital for ongoing care., Conclusion: Prompt diagnosis and surgical treatment are essential to improve patient outcomes. The unique aspect of this case is the persistence of the methicillin-sensitive Staphylococcus aureus infection. Centralized surgical services are pivotal in conjunction with robust antimicrobial regimens., Lesson: This case reinforces the importance of high clinical suspicion of an unknown source of sepsis., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Bovine mastitis is a prevalent infectious disease in dairy herds worldwide, resulting in substantial economic losses. Staphylococcus aureus is a major cause of mastitis in animals, and its antibiotic resistance poses challenges for treatment. Recently, renewed interest has focused on the development of alternative methods to antibiotic therapy, including bacteriophages (phages), for controlling bacterial infections. In this study, 2 lytic phages, vB_SauM_JDYN (JDYN) and vB_SauM_JDF86 (JDF86), were isolated from the cattle sewage effluent samples collected from dairy farms in Shanghai. The 2 phages have a broad bactericidal spectrum against Staphylococcus of various origins. Genomic and morphological analyses revealed that the 2 phages belonged to the Myoviridae family. Moreover, JDYN and JDF86 remained stable under a wide temperature and pH range and were almost unaffected in chloroform. In this study, we prepared a phage cocktail (PHC-1) which consisted of a 1:1:1 ratio of JDYN, JDF86, and SLPW (a previously characterized phage). We found that PHC-1 showed the strongest bacteriolytic effect and the lowest frequency of emergence of bacteriophage insensitive mutants compared with monophages. Bovine mammary epithelial cells and lactating mice mastitis models were used to evaluate the effectiveness of PHC-1 in vitro and in vivo, respectively. The results demonstrated that PHC-1 treatment significantly reduced bacterial load, alleviated inflammatory response, and improved mastitis pathology. Altogether, these results suggest that PHC-1 has the potential to treat S. aureus-induced bovine mastitis and that phage cocktails can combat antibiotic-resistant S. aureus infections., (© 2024, The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Bacterial infections and excessive inflammation present substantial challenges for clinical wound healing. Hydrogels with mild photothermal (PTT) effects have emerged as promising agents owing to their dual actions: positive effects on cells and negative effects on bacteria. Here, an injectable self-healing hydrogel of oxidized konjac glucomannan/arginine-modified chitosan (OKGM/CS-Arg, OC) integrated with protocatechualdehyde-@Fe (PF) nanoparticles capable of effectively absorbing near-infrared radiation is synthesized successfully. The OC/PF hydrogels exhibit excellent mechanical properties, biocompatibility, and antioxidant activity. Moreover, in synergy with PTT, OC/PF demonstrates potent antibacterial effects while concurrently stimulating cell migration and new blood vessel formation. In methicillin-resistant Staphylococcus aureus-infected full-thickness mouse wounds, the OC/PF hydrogel displays remarkable antibacterial and anti-inflammatory activities, and accelerates wound healing by regulating the wound immune microenvironment and promoting M2 macrophage polarization. Consequently, the OC/PF hydrogel represents a novel therapeutic approach for treating multidrug-resistant bacterial infections and offers a technologically advanced solution for managing infectious wounds in clinical settings., (© 2024 Wiley‐VCH GmbH.)

Background: This paper reports a 10-year series of spontaneous nasal septal abscesses in immune-competent children, with suggestions for optimal management., Methods: A retrospective case note review was conducted of children undergoing an operation for incision and drainage of nasal septal abscesses between 2013 and 2023., Results: Six children were identified via electronic hospital records during the 10-year review period, five with a spontaneous abscess. The children were aged 10-14 years. All were immunocompetent and none had active sinus infection. The most common presenting features were nasal swelling, facial swelling, headache, nasal congestion and fever. The most common bacterial isolate was Staphylococcus aureus . All children received prompt surgical drainage and intravenous antibiotic therapy. Complications were seen in three children, with one child developing significant intracranial complications., Conclusion: To our knowledge, this is the first series of spontaneous nasal septal abscesses in immunocompetent children. The high prevalence of Staphylococcus aureus suggests spread from the nasal mucosa or vestibule. Early recognition, computed tomography scanning, surgical drainage and antibiotic therapy are the mainstays of treatment, to prevent potentially life-threatening complications.

BACKGROUND Facet joint septic arthritis (SAFJ) is a rare clinical entity that is extremely challenging to diagnose, often presenting unilaterally and with nonspecific clinical symptoms. However, SAFJ has significant morbidity and mortality, especially with delayed diagnosis. It becomes all the more important for the clinician to recognize that SAFJ can present bilaterally and be associated with direct inoculation, such as in acupuncture. CASE REPORT A 53-year-old woman with chronic alcoholism and well-controlled type 2 diabetes mellitus was initially admitted for progressively worsening atraumatic lower back pain. Initial non-contrast magnetic resonance imaging (MRI) of the lumbar spine revealed bilateral L4-L5 and L5-S1 nonspecific facet joint effusions. Clinical examination was unremarkable. Biochemically, the patient had mildly elevated inflammatory markers. She was treated conservatively with close outpatient follow-up. However, her back pain progressively worsened, with new-onset lower limb weakness and numbness. Repeat MRI showed L4-L5 bilateral facet joint fluid collection with adjacent bony destruction, as well as posterior paraspinal and epidural fluid collections compatible with L4-L5 bilateral SAFJ with paraspinal and epidural abscesses. Urgent surgical drainage and bilateral lateral facet decompression was performed. Intraoperative cultures revealed methicillin-sensitive Staphylococcus aureus as the causative organism. Postoperatively, 6 weeks of intravenous and oral antibiotics were given with good recovery. CONCLUSIONS We describe a case of bilateral SAFJ following acupuncture that was initially missed. With the increasing prevalence of acupuncture treatment for lower back pain, bilateral SAFJ should be a diagnostic consideration. Detailed clinical history is key; this, as well as a high index of suspicion, early evaluation and treatment, are essential to obtain a favorable outcome.

Skin and soft tissue infections (SSTIs) represent a significant healthcare challenge, particularly in the context of increasing antibiotic resistance. This study investigates the efficacy of a novel therapeutic approach combining bacteriophage (phage) therapy with a gum Karaya (GK)-based hydrogel delivery system in a porcine model of deep staphylococcal SSTIs. The study exploits the lytic activity and safety of the Staphylococcus phage 812K1/420 of the Kayvirus genus, which is active against methicillin-resistant Staphylococcus aureus (MRSA). The GK injectable hydrogels and hydrogel films, developed by our research group, serve as effective, non-toxic, and easy-to-apply delivery systems, supporting moist wound healing and re-epithelialization. In the porcine model, the combined treatment showed asynergistic effect, leading to a significant reduction in bacterial load (2.5 log CFU/gram of tissue) within one week. Local signs of inflammation were significantly reduced by day 8, with clear evidence of re-epithelialization and wound contraction. Importantly, no adverse effects of the GK-based delivery system were observed throughout the study. The results highlight the potential of this innovative therapeutic approach to effectively treat deep staphylococcal SSTIs, providing a promising avenue for further research and clinical application in the field of infections caused by antibiotic-resistant bacteria., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Staphylococcus aureus is a pathogenic bacterium responsible for a broad spectrum of infections, including cutaneous, respiratory, osteoarticular, and systemic infections. It poses a significant clinical challenge due to its ability to develop antibiotic resistance. This resistance limits therapeutic options, increases the risk of severe complications, and underscores the urgent need for new strategies to address this threat, including the investigation of treatments complementary to antibiotics. The evaluation of novel antimicrobial agents often employs animal models, with the zebrafish embryo model being particularly interesting for studying host-pathogen interactions, establishing itself as a crucial tool in this field. For the first time, this study presents a zebrafish embryo model for the in vivo assessment of bacteriophage efficacy against S. aureus infection. A localized infection was induced by microinjecting either methicillin-resistant S. aureus (MRSA) or methicillin-susceptible S. aureus (MSSA). Subsequent treatments involved administering either bacteriophage, vancomycin (the reference antibiotic for MRSA), or a combination of both via the same route to explore potential synergistic effects. Our findings indicate that the bacteriophage was as effective as vancomycin in enhancing survival rates, whether used alone or in combination. Moreover, bacteriophage treatment appears to be even more effective in reducing the bacterial load in S. aureus -infected embryos post-treatment than the antibiotic. Our study validates the use of the zebrafish embryo model and highlights its potential as a valuable tool in assessing bacteriophage efficacy treatments in vivo ., Competing Interests: The authors declare no conflict of interest.

Bacterial infections pose a global concern due to high fatality rates, particularly with the rise of drug-resistant bacteria and biofilm formation. There is an urgent need for innovative strategies to combat this issue. A study on chemodynamic therapy (CDT) using nanozymes in conjunction with photothermal therapy (PTT) has displayed potential in addressing drug-resistant bacterial infections. However, the effectiveness of this combined approach is limited by inadequate light absorption. This work suggests the NiOx nanoparticles enriched with oxygen vacancies enhance CDT and PTT to overcome this challenge. The presence of oxygen vacancies in NiOx can reduce the energy gap between its valence band and conduction band, facilitating oxygen adsorption. NiOx has exhibited notable antibacterial properties and complete eradication of biofilms in both laboratory and animal trials. In animal abscess models, NiOx demonstrated antibacterial and anti-inflammatory effects in the initial stages, while also promoting wound healing and tissue regeneration by influencing immune factors and encouraging collagen deposition and neovascularization. With positive biosafety and biocompatibility profiles, the oxygen vacancy-enhanced CDT and PTT therapy proposed in this article hold promise for effective sterilization, deep biofilm removal, and treatment of infections caused by drug-resistant bacteria. STATEMENT OF SIGNIFICANCE: This study constructs oxygen vacancies NiOx nanoparticles (NiOx NPs) to improve the efficacy of photothermal therapy and chemodynamic therapy. The presence of oxygen vacancies in NiOx NPs helps bridge the energy gap between its valence band and conduction band, facilitating oxygen adsorption and improving catalytic efficiency. In both in vivo and in vitro antibacterial experiments, NiOx NPs demonstrate effective antibacterial and anti-inflammatory properties. Furthermore, it aids in wound healing and tissue regeneration by modulating immune factors, collagen deposition, and angiogenesis. This approach presents a promising collaborative strategy for utilizing nickel-based defective nanomaterials in combating deep drug-resistant bacterial infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Due to the advanced studies on stem cells in developmental biology, the roles of stem cells in the body and their phenotypes in related diseases have not been covered clearly. Meanwhile, with the intensive research on the mechanisms of stem cells in regulating various diseases, stem cell therapy is increasingly being attention because of its effectiveness and safety. As one of the most widely used stem cell in stem cell therapies, hematopoietic stem cell transplantation shows huge advantage in treatment of leukemia and other blood-malignant diseases. Besides, due to the effect of anti-inflammatory and immunomodulatory, mesenchymal stem cells could be a potential therapeutic strategy for variety infectious diseases. In this review, we summarized the effects of Staphylococcus aureus (S. aureus) and its components on different types of adult stem cells and their downstream signaling pathways. Also, we reviewed the roles of different kinds of stem cells in various disease models caused by S. aureus, providing new insights for applying stem cell therapy to treat infectious diseases., (© 2024. The Author(s).)

Metal-implant associated bacterial infections are a major clinical problem due to antibiotic treatment failure. As an alternative, we determined the effects of bacteriophage ISP on clinical isolates of Staphylococcus aureus in various stages of its life cycle in relation to biofilm formation and maturation. ISP effectively eliminated all planktonic phase bacteria, whereas its efficacy was reduced against bacteria attached to the metal implant and bacteria embedded within biofilms. The biofilm architecture hampered the bactericidal effects of ISP, as mechanical disruption of biofilms improved the efficacy of ISP against the bacteria. Phages penetrated the biofilm and interacted with the bacteria throughout the biofilm. However, most of the biofilm-embedded bacteria were phage-tolerant. In agreement, bacteria dispersed from mature biofilms of all clinical isolates, except for LUH15394, tolerated the lytic activity of ISP. Lastly, persisters within mature biofilms tolerated ISP and proliferated in its presence. Based on these findings, we conclude that ISP eliminates planktonic phase Staphylococcus aureus while its efficacy is limited against bacteria attached to the metal implant, embedded within (persister-enriched) biofilms, and dispersed from biofilms., (© 2024. The Author(s).)

We present a case of deep surgical site infection (SSI) at a spinal cord stimulator (SCS) trial implantation site, resulting from an allergic reaction to an unknown agent. A 38-year-old female with complex regional pain syndrome began an SCS trial, noting 100% pain relief for 5 days. Fluid drainage from the surgical site was reported on POD6 and trial leads were removed the following day. The patient was hospitalized with sepsis. Blood cultures revealed Staphylococcus aureus . MRIs showed skin breakdown and cellulitis of the paraspinal musculature extending into the epidural space. The patient was maintained with antibiotics and rigorous wound care for 9 days and the surgical site infection resolved. The patient proceeded to SCS implantation, and reported good pain relief with the implanted device.

Bacterial infections trigger inflammation and impede the closure of skin wounds. The misuse of antibiotics exacerbates skin infections by generating multidrug-resistant bacteria. In this study, we developed chemo-photothermal therapy (chemo-PTT) based on near-infrared (NIR)-irradiated chitosan/gold nanorod (GNR) clusters as anti-methicillin-resistant Staphylococcus aureus (MRSA) agents. The nanocomposites exhibited an average size of 223 nm with a surface charge of 36 mV. These plasmonic nanocomposites demonstrated on-demand and rapid hyperthermal action under NIR. The combined effect of positive charge and PTT by NIR-irradiated nanocomposites resulted in a remarkable inhibition rate of 96 % against planktonic MRSA, indicating a synergistic activity compared to chitosan nanoparticles or GNR alone. The nanocomposites easily penetrated the biofilm matrix. The combination of chemical and photothermal treatments by NIR-stimulated clusters significantly damaged the biofilm structure, eradicating MRSA inside the biomass. NIR-irradiated chitosan/GNR clusters increased the skin temperature of mice by 13 °C. The plasmonic nanocomposites induced negligible skin irritation in vivo. In summary, this novel nanosystem demonstrated potent antibacterial effects against planktonic and biofilm MRSA, showcasing the possible efficacy in treating skin infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) emphasises the urgent need for novel antimicrobial agents as alternatives to antibiotics. Bacteriophage therapy is one of the most promising antimicrobial strategies. Here, we isolated and comprehensively characterized a novel Staphylococcus phage, vB_SauM_VL10 (VL10), from urban sewage. The VL10 genome displays 141,746 bp of linear double-stranded DNA, containing 193 open reading frames and lacking tRNA, virulence, or antibiotic resistance genes. Phylogenetic analysis categorizes VL10 as a novel species within the Silviavirus genus, Twortvirinae subfamily. VL10 exhibits lytic behaviour characterized by efficient adsorption, a short latent period, and substantial burst size, with environmental stability. It demonstrates lytic activity against 79.06% of tested S. aureus strains, highlighting its species specificity. Additionally, VL10 effectively targets MRSA biofilms, reducing biomass and viable cells. In MRSA-infected G. mellonella larvae, VL10 enhances survival rates, supporting its potential for phage therapy applications. Moreover, the emergence of VL10-resistant S. aureus strains associated with fitness trade-offs, including reduced growth, biofilm formation, and virulence. Altogether, these findings emphasize VL10 as a promising candidate for developing therapeutic agents against MRSA infections, providing insights into phage biology and resistance dynamics., (© 2024. The Author(s).)

Osteomyelitis caused by deep tissue infections is difficult to cure through phototherapy due to the poor penetration depth of the light. Herein, Cu/C/Fe 3 O 4 -COOH nanorod composites (Cu/C/Fe 3 O 4 -COOH) with nanoscale tip convex structures are successfully fabricated as a microwave-responsive smart bacteria-capture-killing vector. Cu/C/Fe 3 O 4 -COOH exhibited excellent magnetic targeting and bacteria-capturing ability due to its magnetism and high selectivity affinity to the amino groups on the surface of Staphylococcus aureus (S. aureus). Under microwave irradiation, Cu/C/Fe 3 O 4 -COOH efficiently treated S. aureus-infected osteomyelitis through the synergistic effects of microwave thermal therapy, microwave dynamic therapy, and copper ion therapy. It is calculated the electric field intensity in various regions of Cu/C/Fe 3 O 4 -COOH under microwave irradiation, demonstrating that it obtained the highest electric field intensity on the surface of copper nanoparticles of Cu/C/Fe 3 O 4 -COOH due to its high-curvature tips and metallic properties. This led to copper nanoparticles attracted more charged particles compared with other areas in Cu/C/Fe 3 O 4 -COOH. These charges are easier to escape from the high curvature surface of Cu/C/Fe 3 O 4 -COOH, and captured by adsorbed oxygen, resulting in the generation of reactive oxygen species. The Cu/C/Fe 3 O 4 -COOH designed in this study is expected to provide insight into the treatment of deep tissue infections under the irradiation of microwave., (© 2023 Wiley‐VCH GmbH.)

Staphylococcus epidermidis is a common member of the human skin and nose microbiomes and a frequent cause of invasive infections. Transducing phages accomplish the horizontal transfer of resistance and virulence genes by mispackaging of mobile-genetic elements, contributing to severe, therapy-refractory S. epidermidis infections. Lytic phages on the other hand can be interesting candidates for new anti-S. epidermidis phage therapies. Despite the importance of phages, we are only beginning to unravel S. epidermidis phage interactions. Recent studies shed new light on S. epidermidis phage diversity, host range, and receptor specificities. Modulation of cell wall teichoic acids, the major phage receptor structures, along with other phage defense mechanisms, are crucial determinants for S. epidermidis susceptibility to different phage groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Staphylococcus aureus fracture-related infections (FRIs) are associated with significant morbidity in part because conventional antibiotic therapies have limited ability to eradicate S. aureus in sessile states. Therefore, the objective of this study was to assess the feasibility of using Staphylococcal bacteriophages for FRI by testing the activity of a library of Staphylococcal bacteriophage therapeutics against historically preserved S. aureus FRI clinical isolates., Methods: Current Procedural Terminology codes were used to identify patients with FRI from January 1, 2021 to December 31, 2021. Preserved S. aureus FRI isolates from the cases were then tested against a library of 51 Staphylococcal bacteriophages from an American company. This was conducted by assessing the ability of bacteriophages to reduce bacterial growth over time. Growth inhibition greater than 16 h was considered adequate for this study., Results: All of the S. aureus preserved clinical isolates had at least one bacteriophage with robust lytic activity and six bacteriophages (11.8 %) had robust lytic activity to seven or more of the clinical isolates. However, 41 of the bacteriophages (80.4 %) had activity to less than three of the clinical isolates and no bacteriophage had activity to all the clinical isolates., Conclusion: Our findings show that Staphylococcal bacteriophage therapeutics are readily available for S. aureus FRI clinical isolates. However, when correlated with the current barriers to using bacteriophages to treat FRI, designated Staphylococcal bacteriophage cocktails with broad spectrum activity should be created., Competing Interests: Declaration of competing interest J. B. Doub was a previous consultant with Adaptive Phage Therapeutics and currently is receiving a grant (13582210) from the National Institutes of Health. J. Fackler is an employee of Adaptive Phage Therapeutics. R. V. O'Toole is a paid consultant for Stryker, receives stock options from Imagen, and receives royalties from Lincotek, all unrelated to this research. The remaining authors report no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Staphylococcus aureus is one of the most common infectious agents, causing morbidity and mortality worldwide. Most pathogenic bacteria are classified in the group of mesophilic bacteria and the optimal growth temperature of these bacteria changes between 33 and 41 °C. Increased temperature can inhibit bacterial growth and mobility, which in turn, can trigger autolysis and cause cell wall damage. Hyperthermia treatment is defined as a heat-mediated treatment method applied using temperatures higher than body temperature. Nowadays, this treatment method is used especially in the treatment of tumours. Hyperthermia treatment is divided into two groups: mild hyperthermia and ablative or high-temperature hyperthermia. Mild hyperthermia is a therapeutic technique in which tumour tissue is heated above body temperature to produce a physiological or biological effect but is often not aimed at directly causing significant cell death. The goal of this method is to achieve temperatures of 40-45 °C in human tissues for up to 2 h. Hyperthermia can be used in the treatment of infections caused by such bacterial pathogens. In addition, using hyperthermia in combination with antimicrobial drugs may result in synergistic effects and reduce resistance issues. In our study, we used two different temperature levels (37 °C and 45 °C). We assessed growth inhibition, some virulence factors, alteration colony morphologies, and antimicrobial susceptibility for several antibiotics with three methods (Kirby-Bauer, E-test and broth microdilution) under hyperthermia. In the study, we observed that hyperthermia affected the urease enzyme, antibiotic sensitivity levels showed synergy with hyperthermia, and changes occurred in colony diameters and affected bacterial growth. We hypothesise that hyperthermia might be a new therapeutic option for infectious diseases as a sole agent or in combination with different antimicrobials., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In recent years, the emergence of multidrug-resistant bacteria has limited the selection of drugs for treating bacterial infections, reduced clinical efficacy, and increased treatment costs and mortality. It is urgent to find alternative antibiotics. In order to explore a new method for controlling methicillin-resistant Staphylococcus aureus (S. aureus), this study isolated and purified a multidrug-resistant S. aureus broad-spectrum phage JPL-50 from wastewater. JPL-50 belongs to the Siphoviridae family after morphological observation, biological characterization, and transmission electron microscopy (TEM) fragmentation spectrum analysis. It can cleave 84% of tested S. aureus (168/200), in which 100% of tested mastitis-associated strains (48/48) and 72.04% of MRSA strains (67/93) were lysed. In addition, it has an optimal growth temperature of about 30°C, a high activity within a wide pH range (pH 3-10), and an optimal multiplicity of infection of 0.01. The one-step growth curve shows a latent time of 20 min, an explosive time of 80 min. JPL-50 was 16 927 bp in length and was encoded by double-stranded DNA, with no genes associated with bacterial resistance or virulence factors detected. In a therapeutic study, injection of the phage JPL-50 once and for 7 times in 7 days protected 40% and 60% of the mice from fatal S. aureus infection, respectively. More importantly, JPL-50-doxycycline combination could effectively inhibit host S. aureus in vitro and reduce the use of doxycycline within 8 h. In conclusion, the bacteriophage JPL-50 has a wide lysis spectrum, high lysis rate, high tolerance to extreme environments, and moderate in vivo activity, providing ideas for developing multidrug-resistant S. aureus infections., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

Background: Personalized clinical management of spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE) is challenging due to limited evidence of microbiologic findings and their clinical impact during the clinical course of the disease. We aimed to characterize clinico-microbiological and imaging phenotypes of SD and ISEE to provide useful insights that could improve outcomes and potentially modify guidelines., Methods: We performed chart review and collected data on the following parameters: bacterial antibiogram-resistogram, type of primary spinal infection, location of spinal infection, source of infection, method of detection, clinical complications (sepsis, septic embolism, and endocarditis), length of hospital and intensive care unit (ICU) stay, relapse rate, and disease-related mortality in patients with proven pyogenic SD and ISEE treated surgically in a university hospital in Germany between 2002 and 2022., Results: We included data from 187 patients (125 SD, 66.8% and 62 ISEE, 33.2%). Gram-positive bacteria (GPB) were overall more frequently detected than gram-negative bacteria (GNB) (GPB: 162, 86.6% vs. GNB: 25, 13.4%, p < 0.001). Infective endocarditis was caused only by GPB (GPB: 23, 16.5% vs. GNB: 0, 0.0%, p = 0.046). Methicillin-susceptible Staphylococcus aureus was the most frequently isolated strain (MSSA: n = 100, 53.5%), occurred more frequently in the cervical spine compared to other bacteria (OB) (MSSA: 41, 41.0% vs. OB: 18, 20.7%, p = 0.004) and was most frequently detected in patients with skin infection as the primary source of infection (MSSA: 26, 40.6% vs. OB: 11, 16.7%, p = 0.002). Streptococcus spp. and Enterococcus spp. (SE: n = 31, 16.6%) were more often regarded as the cause of endocarditis (SE: 8, 27.6% vs. OB: 15, 11.4%, p = 0.037) and were less frequently detected in intraoperative specimens (SE: 19, 61.3% vs. OB: 138, 88.5%, p < 0.001). Enterobacterales (E: n = 20, 10.7%) were identified more frequently in urinary tract infections (E: 9, 50.0% vs. OB: 4, 3.6%, p < 0.001). Coagulase-negative Staphylococci (CoNS: n = 20, 10.7%) were characterized by a lower prevalence of sepsis (CoNS: 4, 20.0% vs. OB: 90, 53.9%, p = 0.004) and were more frequently detected in intraoperative specimens (CoNS: 20, 100. 0% vs. OB: 137, 82.0%, p = 0.048). Moreover, CoNS-associated cases showed a shorter length of ICU stay (CoNS: 2 [1-18] days vs. OB: 6 [1-53] days, median [interquartile range], p = 0.037), and occurred more frequently due to foreign body-associated infections (CoNS: 8, 61.5% vs. OB: 15, 12.8%, p = 0.008). The presence of methicillin-resistant Staphylococcus aureus (MRSA) prolonged hospital stay by 56 [24-58] days and ICU stay by 16 [1-44] days, whereas patients with Pseudomonas aeruginosa spent only 20 [18-29] days in the hospital and no day in the ICU 0 [0-5] days., Conclusions: Our retrospective cohort study identified distinct bacterial-specific manifestations in pyogenic SD and ISEE regarding clinical course, neuroanatomic targets, method of pathogen detection, and sources of infection. The clinico-microbiological patterns varied depending on the specific pathogens., (© 2023. The Author(s).)

Introduction: Infections related to deep brain stimulation (DBS) can lead to discontinuation of the treatment and increased morbidity. Various measures of reducing infection rates have been proposed in the literature, but scientific consensus is lacking. The aim of this study was to report a 26-year single center experience of DBS infections and provide recommendations for the prevention and management of them., Methods: The retrospective analysis consisted of 978 DBS surgeries performed at Oulu University Hospital (OUH) from 1997 to 2022. This included 342 primary or reimplantations of DBS electrodes and 559 primary or reimplantations of implantable pulse generator (IPG). Infections within approximately 1 year after the surgery without secondary cause were considered surgical-site infections (SSIs). χ2 test was used to compare infection rates before and after 2013, when the systematic implementation of infection prevention measures was started., Results: A total of 35 DBS implants were found to be infected. The number of SSIs was 30, of which 29 were originally operated in OUH leading to a center-specific infection rate of 3.1%. Of the SSIs, 17.2% occurred after IPG replacement. Staphylococcus aureus was found in 75.0% of cultures and 32.1% were mixed infections. The treatment of SSIs included aggressive surgical revision combined with cefuroxime and vancomycin antibiotics, as most patients in the initial conservative treatment group eventually required surgical revision. A statistically significant difference in infection rates before and after the implementation of preventative measures was not observed (risk ratio 2.20, 95% confidence interval 0.94-5.75, p = 0.051), despite over two-fold difference in the incidence of SSIs., Conclusion: Our findings show that the rates of surgical infections are low in modern DBS, but due to their serious consequences, preventative measures should be implemented. We highlight that mixed infections should be accounted for in the antibiotic selection. Furthermore, our treatment recommendation includes aggressive surgical revision combined with antibiotic treatment., (© 2024 S. Karger AG, Basel.)

Staphylococcus sp. is the most common bacterial genus in infections related to diabetic foot ulcers (DFUs). The emergence of multidrug-resistant bacteria places a serious burden on public health systems. Phage therapy is an alternative treatment to antibiotics, overcoming the issue of antibiotic resistance. In this study, six phages (SAVM01 to SAVM06) were isolated from effluents and were used against a panel of staphylococcal clinical samples isolated from DFUs. A genomic analysis revealed that the phages belonged to the Herelleviridae family, with sequences similar to those of the Kayvirus genus. No lysogeny-associated genes, known virulence or drug resistance genes were identified in the phage genomes. The phages displayed a strong lytic and antibiofilm activity against DFU clinical isolates, as well as against opportunistic pathogenic coagulase-negative staphylococci. The results presented here suggest that these phages could be effective biocontrol agents against staphylococcal clinical isolates from DFUs.

S. aureus is a pathogen that frequently causes severe morbidity and phage therapy is being discussed as an alternative to antibiotics for the treatment of S. aureus infections. In this in vitro and animal study, we demonstrated that the activity of anti-staphylococcal phages is severely impaired in 0.5% plasma or synovial fluid. Despite phage replication in these matrices, lysis of the bacteria was slower than phage propagation, and no reduction of the bacterial population was observed. The inhibition of the phages associated with a reduction in phage adsorption, quantified to 99% at 10% plasma. S. aureus is known to bind multiple coagulation factors, resulting in the formation of aggregates and blood clots that might protect the bacterium from the phages. Here, we show that purified fibrinogen at a sub-physiological concentration of 0.4 mg/ml is sufficient to impair phage activity. In contrast, dissolution of the clots by tissue plasminogen activator (tPA) partially restored phage activity. Consistent with these in vitro findings, phage treatment did not reduce bacterial burdens in a neutropenic mouse S. aureus thigh infection model. In summary, phage treatment of S. aureus infections inside the body may be fundamentally challenging, and more investigation is needed prior to proceeding to in-human trials., (© 2023. Springer Nature Limited.)

Introduction: New Zealand (NZ) has high rates of pediatric acute hematogenous osteomyelitis (AHO) with males and children of Pasifika and Māori ethnicity overrepresented., Aims: To update the incidence of Pediatric AHO over 10 years, identifying trends in presentation, organisms, treatment, and outcomes., Methods: A 10-year retrospective review of children aged 6 weeks to 15 years admitted with Pediatric AHO across two centers from 2008 to 2017. Demographic data, features of presentation, investigations, management, and complications were collected. Incidence was calculated from census data. Data were compared with our osteomyelitis database from the previous decade. (1)., Results: 796 cases were identified. The incidence was 18 per 100,000 per annum. The average age was 7.7 years. Pasifika and Māori children are overrepresented (57%). 370 children (51%) came from low socioeconomic areas. Methicillin-sensitive Staphylococcus aureus was the most common pathogen (87%). Methicillin-resistant Staphylococcus aureus (MRSA) rates are low (4.4%). Forty-four (5.5%) children were admitted to the Pediatric Intensive Care Unit (PICU) with 9% mortality. The mean duration of antibiotics was 40 days. 325 children (41%) had surgery. Chronic infection has increased from 1.7% to 5.7%., Conclusions: NZ has high rates of AHO, however, the incidence has decreased from the previous decade. Males, those in low socioeconomic areas, Pasifika and Māori have high disease burden. The use of MRI as a diagnostic modality has increased. Future studies should focus on improving treatment via prospective analysis and reporting long-term morbidity to improve outcomes for children with severe disease and reduce rates of chronic infection., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purposes: The purpose of this study was to present and analyze the etiologic factors, clinical manifestations, bacteriology, and treatment outcomes of nasal septal abscess in a large cohort of adult patients., Material and Methods: Retrospective analysis., Results: 36 adult patients, age from 19 to 85 (mean age, 51.83), with nasal septal abscesses were treated at Ear Nose Throat Hospital of Ho Chi Minh City from January 2020 to August 2022. The most common symptoms were nasal obstruction (75 %), headache/facial pain (58.33 %). Etiologic factors were found in 83.33 % of cases with the most common were diabetes mellitus (47.22 %), nose-picking (44.44 %). 75 % of cases had positive bacterial culture, of which 70.37 % were Staphylococcus aureus. Septal abscess was successfully treated in all cases using our treatment protocol, which involved an extended modified Killian's incision, irrigation with 1 % poviodine, placement of gauze in the abscess pocket, and nasal packing with Merocels., Conclusions: Diabetes and nose-picking were the most common etiologic factors; Staphylococcus aureus was the most common organism of nasal septal abscess in our study. Our treatment protocol is safe and effective., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

The issue of antibiotic resistance in healthcare worldwide has led to a pressing need to explore and develop alternative approaches to combat infectious diseases. Among these methods, phage therapy has emerged as a potential solution to tackle this growing challenge. Virulent phages of the Herelleviridae family, known for their ability to cause lysis of Staphylococcus aureus , a clinically significant pathogen frequently associated with multidrug resistance, have proven to be one of the most effective viruses utilized in phage therapy. In order to utilize phages for therapeutic purposes effectively, a thorough investigation into their physiology and mechanisms of action on infected cells is essential. The use of omics technologies, particularly total RNA sequencing, is a promising approach for analyzing the interaction between phages and their hosts, allowing for the assessment of both the behavior of the phage during infection and the cell's response. This review aims to provide a comprehensive overview of the physiology of the Herelleviridae family, utilizing existing analyses of their total phage transcriptomes. Additionally, it sheds light on the changes that occur in the metabolism of S. aureus when infected with virulent bacteriophages, contributing to a deeper understanding of the phage-host interaction.

Background: Infective arthritis is an orthopaedic surgical emergency. Staphylococcus aureus remains the commonest causative bacteria across all age groups. Prevotella spp. as a cause of infective arthritis is extremely rare., Case Report: We present our case of a 30-year-old African male patient who presented with mild signs of infective arthritis of the left hip. His risk factors were his background retroviral disease, intravenous drug abuse, and a previous episode of left hip arthrotomy which healed expectantly with intervention. The current presentation was treated with arthrotomy of the hip, fluid lavage, and skeletal traction based on our clinical findings and the rarity of the presentation was seen to be mobilising non-weight bearing with crutches, and pain-free on the left hip., Conclusion: A high index of suspicion for Prevotella Septic Arthritis (PSA) should be exercised when treating infective arthritis patients with background joint arthropathies, and intravenous drug abuse, especially in individuals with significant immunosuppression and/or recent tooth extraction. Fortunately, although rare an entity, good outcomes can be expected with early diagnosis and classic treatment principles of joint decompression and lavage as well as guided antibiotic therapy., (© 2023. The Author(s).)

Prosthetic valve endocarditis (PVE) remains a serious condition with a high mortality rate. Precise identification of the PVE-associated pathogen/s and their virulence is essential for successful therapy and patient survival. The commonly described PVE-associated pathogens are staphylococci, streptococci, and enterococci, with Staphylococcus aureus being the most frequently diagnosed species. Furthermore, multi-drug resistance pathogens are increasing in prevalence and continue to pose new challenges mandating a personalized approach. Blood cultures in combination with echocardiography are the most common methods to diagnose PVE, often being the only indication, it exists. In many cases, the diagnostic strategy recommended in the clinical guidelines does not identify the precise microbial agent, and frequently, false-negative blood cultures are reported. Despite the fact that blood culture findings are not always a good indicator of the actual PVE agent in the valve tissue, only a minority of re-operated prostheses are subjected to microbiological diagnostic evaluation. In this review, we focus on the diversity and the complete spectrum of PVE-associated bacterial, fungal, and viral pathogens in blood and prosthetic heart valve, their possible virulence potential, and their challenges in making a microbial diagnosis. We are curious to understand if the unacceptable high mortality of PVE is associated with the high number of negative microbial findings in connection with a possible PVE. Herein, we discuss the possibilities and limits of the diagnostic methods conventionally used and make recommendations for enhanced pathogen identification. We also show possible virulence factors of the most common PVE-associated pathogens and their clinical effects. Based on blood culture, molecular biological diagnostics, and specific valve examination, better derivations for the antibiotic therapy as well as possible preventive intervention can be established in the future., Competing Interests: Conflict of interest: There is no conflicts of interest of the authors who worked on this publication., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Phage therapy has been successfully used as an experimental therapy in the treatment of multidrug-resistant strains of Staphylococcus aureus (MDRSA)-caused skin infections and is seen as the most promising alternative to antibiotics. However, in recent years a number of reports indicating that phages can interact with eukaryotic cells emerged. Therefore, there is a need to re-evaluate phage therapy in light of safety. It is important to analyze not only the cytotoxicity of phages alone but also the impact their lytic activity against bacteria may have on human cells. As progeny virions rupture the cell wall, lipoteichoic acids are released in high quantities. It has been shown that they act as inflammatory agents and their presence could lead to the worsening of the patient's condition and influence their recovery. In our work, we have tested if the treatment of normal human fibroblasts with staphylococcal phages will influence the metabolic state of the cell and the integrity of cell membranes. We have also analyzed the effectiveness of bacteriophages in reducing the number of MDRSA attached to human fibroblasts and the influence of the lytic activity of phages on cell viability. We observed that, out of three tested anti- Staphylococcal phages-vB&#95;SauM-A, vB&#95;SauM-C and vB&#95;SauM-D-high concentrations (10 9 PFU/mL) of two, vB&#95;SauM-A and vB&#95;SauM-D, showed a negative impact on the viability of human fibroblasts. However, a dose of 10 7 PFU/mL had no effect on the metabolic activity or membrane integrity of the cells. We also observed that the addition of phages alleviated the negative effect of the MDRSA infection on fibroblasts' viability, as phages were able to effectively reduce the number of bacteria in the co-culture. We believe that these results will contribute to a better understanding of the influence of phage therapy on human cells and encourage even more studies on this topic.

Introduction: Staphylococcus aureus (SA) is a major human bacterial pathogen increasingly refractory to antibiotics. Given the dearth of novel antibiotics in the developmental pipeline, we require concerted efforts at optimizing novel antimicrobial approaches. One promising option is the utilization of bacteriophage (phage) therapy, which has been resurrected as a viable clinical therapeutic. Specifically, an expanded library of phages targeting SA is desired. We surmised that SA-targeting phages would be readily accessible as a major component of the cutaneous microbiome. Specifically, we sought to discern if easily accessible (convenient) and discrete anatomic locations, including the nares, axilla, fingernails, toenails, and web spaces, could provide intact phages via a noninvasive, expedient procedure involving swabbing., Methods: One hundred subjects participated in systematic skin swab specimen collections. Pooled samples were subject to phage harvesting utilizing the soft agar overlay technique. The approval was secured from the Naval Medical Research Center Institutional Review Board (NMRC 2018.0004 FWA00000152). We utilized the same procedures from known samples containing SA-targeting phages. As another positive control, we employed the same swab and acquired samples from an active wound infection., Results: As anticipated, there were no adverse events, and the procedure was successfully implemented within the projected 10-minute duration. No phages were identified exploiting this methodology. Positive controls from various environmental samples identified SA-targeting phages as did the wound effluent sample., Conclusions: Skin swabbing at multiple anatomic sites from 100 adults yielded insufficient biomass for phage recovery. The negative results provide helpful information for future phage isolation attempts. The lessons learned on why this study failed to isolate phages can be easily utilized by others. With a desire to increase our SA-targeting phage library in pursuit of future clinical trials, and acknowledging the paucity of these phages accessible via traditional recovery from environmental sources, we will next acquire large volumes of wound effluent from confirmed infected wounds with SA to optimize the biomass for phage recovery., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Combating multi-drug resistant bacterial infections should be a universal urgency. The gram- positive Staphylococcus aureus (S. aureus) bacteria are generally harmless; healthy people frequently have them on their skin and nose. These bacteria, for the most part, produce no difficulties or only minor skin diseases. Antibiotics and cleansing of the affected region are usually the treatments of choice. S. aureus can become virulent causing serious infections that may lead to pustules to sepsis or death. Normally, it is thought that antibiotics may solve problems concerning bacterial infection; but unfortunately, Staphylococci have evolved mechanisms to resist drugs. Methicillin-Resistant Staphylococcus aureus (MRSA); both in hospitals and in the community, infections are evolving into dangerous pathogens. Health care practitioners may need to use antibiotics with more adverse effects to treat antibiotic-resistant S. aureus infections. Amid existing efforts to resolve this problem, phage therapy proposes a hopeful alternate to face Staphylococcal infections. When the majority of antibiotics have failed to treat infections caused by multidrug-resistant bacteria, such as methicillin- and vancomycin-resistant S. aureus, phage therapy may be an option. Here, we appraise the potential efficacy, current knowledge on bacteriophages for S. aureus, experimental research and information on their clinical application, and limitations of phage therapy for S. aureus infections., (Copyright © 2023. Published by Elsevier Inc.)

There is widespread interest in using obligately lytic bacteriophages ("phages") to treat human bacterial infections. Among Staphylococcus aureus infections, the USA300 lineage is a frequent cause of invasive disease. We observed that phage K, a model S. aureus myophage, exhibits temperature-sensitive growth on USA300 strains, with the wild-type phage providing poorer growth suppression in broth and forming smaller and fainter plaques at 37 °C vs. 30 °C. We isolated 65 mutants of phage K that had improved plaquing characteristics at 37 °C when compared to the parental phage. In all 65 mutants, this phenotype was attributable to loss-of-function (LoF) mutations in gp102 , which encodes a protein of unknown function that has homologs only among the Herelleviridae (SPO1-like myophages infecting gram-positive bacteria). Additional experiments with representative mutants consistently showed that the temperature-sensitive plaque phenotype was specific to USA300 MRSA strains and that Gp102 disruption was correlated with improved suppression of bacterial growth in broth and improved antibacterial activity in a mouse model of upper respiratory tract infection. The same genotype and in vitro phenotypes could be replicated in close relatives of phage K. Gp102 disruption did not have a detectable effect on adsorption but did delay cell culture lysis relative to wild-type under permissive infection conditions, suggesting that gp102 conservation might be maintained by selective pressure for more rapid replication. Expression of gp102 on a plasmid was toxic to both an MSSA and a USA300 MRSA strain. Molecular modeling predicts a protein with two helix-turn-helix domains that displays some similarity to DNA-binding proteins such as transcription factors. While its function remains unclear, gp102 is a conserved gene that is important to the infection process of Kayvirus phages, and it appears that the manner in which USA300 strains defend against them at 37 °C can be overcome by gp102 LoF mutations.

Infections involving antibiotic resistant Staphylococcus aureus ( S. aureus ) represent a major challenge to successful treatment. Further, although bacteriophages (phages) could be an alternative to antibiotics, there exists a lack of correlation in phage susceptibility results between conventional in vitro and in vivo assays. This discrepancy may hinder the potential implementation of bacteriophage therapy. In this study, the susceptibility of twelve S. aureus strains to three commercial phage cocktails and two single phages was assessed. These S. aureus strains (including ten clinical isolates, five of which were methicillin-resistant) were compared using four assays: the spot test, efficiency of plating (EOP), the optical density assay (all in culture media) and microcalorimetry in human serum. In the spot test, EOP and optical density assay, all cocktails and single phages lysed both methicillin susceptible and methicillin resistant S. aureus strains. However, there was an absence of phage-mediated lysis in high concentrations of human serum as measured using microcalorimetry. As this microcalorimetry-based assay more closely resembles in vivo conditions, we propose that microcalorimetry could be included as a useful addition to conventional assays, thereby facilitating more accurate predictions of the in vivo susceptibility of S. aureus to phages during phage selection for therapeutic purposes.

Staphylococcus virus ΦSA012 has a wide host range and efficient lytic activity. Here, we assessed the biological stability of ΦSA012 against temperature, freeze-thawing, and pH to clinically apply the phage. In addition, inoculation of ΦSA012 through i.p. and i.v. injections into mice revealed that phages were reached the limit of detection in serum and accumulated notably spleens without inflammation at 48 h post-inoculation. Furthermore, inoculation of ΦSA012 through s.c. injections in mice significantly induced IgG, which possesses neutralizing activity against ΦSA012 and other Staphylococcus viruses, ΦSA039 and ΦMR003, but not Pseudomonas viruses ΦS12-3 and ΦR18 or Escherichia viruses T1, T4, and T7 in vitro. Immunoelectron microscopic analysis showed that purified anti-phage IgG recognizes the long-tail fiber of staphylococcus viruses. Although S. aureus inoculation resulted in a 25% survival rate in a mouse i.p. model, ΦSA012 inoculation (i.p.) improved the survival rate to 75%; however, the survival rate of ΦSA012-immunized mice decreased to less than non-immunized mice with phage i.v. injection at a MOI of 100. These results indicated that ΦSA012 possesses promise for use against staphylococcal infections but we should carefully address the appropriate dose and periods of phage administration. Our findings facilitate understandings of staphylococcus viruses for phage therapy., (© 2022. The Author(s).)

Staphylococcus aureus is the main aetiologic agent of osteoarticular infections (OAIs) in paediatric patients. The aim of this prospective unicenter study was to describe the phenotypic and genotypic characteristics of S. aureus isolates obtained from OAIs in paediatric patients admitted to tertiary care hospital. Through a surveillance program called OsteoCode , a multidisciplinary team was created and we identified 27 patients with OAIs caused by S. aureus from 2019 to 2021. The susceptibility profile, virulence factors, biofilm formation, pulsed-field gel electrophoresis (PFGE), clonal complex (CC) and sequence type (ST) were determined. In addition, the clinical characteristics and evolution of the patients presented six months after the diagnosis of OAIs were described. Ninety-two percent of the isolates were methicillin-sensitive S. aureus (MSSA). In methicillin-resistant S. aureus (MRSA), SCC mec- II and SCC mec- V were detected. The pvl gene was only observed in MSSA (18.5%) and was associated with highest fever ( p =0.015), multiple localization ( p= 0.017), and soft tissue sites of infection beyond the bone (pyomyositis, pulmonary abscess) ( p= 0.017). Biofilm formation was detected in 55.6% of isolates. The most common CC were CC5 and CC30 which represent the most common linages for bone and joint infections worldwide. The isolates were distributed in different STs, and ST672 was predominant. MRSA were associated with a longer duration of intravenous treatment and a prolonged hospital stay ( p= 0.023). Recurrent infection occurred in five children and orthopaedic complications in 33.3% of patients. This is the first study that reflects the epidemiology of S. aureus in OAIs in paediatric patients in Mexico; a clear predominance of MSSA distributed in different STs was observed. Our findings highlight that a multidisciplinary team is required for the diagnosis and treatment of OAIs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Aguilar-Gómez, Merida-Vieyra, Isunza-Alonso, Morales-Pirela, Colín-Martínez, Juárez-Benítez, García de la Puente and Aquino-Andrade.)